PROJECT SUMMARY The mammalian prefrontal cortex (PFC) is known to be critical for cognitive control of thoughts and actions, as evidenced by the disruption of normal PFC activity in cognitive diseases such as schizophrenia. Sustained activation of the PFC during cognition appears to depend on input from higher-order thalamic nuclei. These nuclei project strongly to cortical layer 1 (L1), where they can engage both inhibitory neurons and pyramidal cell dendrites. Multiple classes of both dendrites and interneurons are positioned to receive L1 thalamic input, with important consequences for PFC activity. Connections from thalamic input onto pyramidal neuron dendrites could drive dendritic spikes in distinct sub-cellular compartments. Similarly, thalamic input onto locally- projecting vasoactive intestinal peptide (VIP+) or neuron-derived neurotrophic factor (NDNF+) interneurons could drive unique patterns of inhibition within L1. The interaction of these excitatory and inhibitory responses will ultimately shape PFC processing and output. Despite the importance of interactions between the thalamus and PFC for cognitive behavior, the cell-type specific connectivity between them remains largely unknown. This proposal will explore the interaction between excitation and inhibition in L1 of the PFC evoked by input from the thalamus. Aim 1 will identify whether thalamic input to L1 generates spikes in particular dendritic compartments. Aim 2 will examine the responses of inhibitory interneurons in L1 to thalamic stimulation and compare those responses to nearby projection neurons. Aim 3 will test how that inhibition is directed locally onto pyramidal neuron dendrites or other classes of interneurons. Together, this work will provide necessary insights into the mechanisms that allow the thalamus to drive PFC dendritic activity during cognitive tasks that are disrupted in psychiatric illness.